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Calculating Process Capability Of Cleaning Processes: Analysis Of Total Organic

Carbon (TOC) Data

Article · January 2022

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Guest Column | January 10, 2022

Calculating Process Capability Of Cleaning

Processes: Analysis Of Total Organic Carbon
(TOC) Data
By Andrew Walsh, Miquel Romero Obon, and Ovais Mohammad

Part of the Cleaning Validation for the 21st Century series

Our previous article provided background on the concept of process capability and how
it could be used to measure the risk associated with cleaning processes.1 This article will
examine a data set of actual total organic carbon (TOC) swab data collected during
cleaning validation for a pharmaceutical manufacturing facility and will show how much
cleaning process knowledge and cleaning process understanding can be easily obtained
through some simple statistical evaluations of such data.

This analysis will also reveal how the adoption of cleaning process capability as a
measure of cleaning risk will not allow for the "relaxation of cleaning efforts,"
which has been a concern of regulators with the implementation of the health-based
exposure limit (HBEL) after the EMA abandoned the historical non-health-based
approaches (i.e., 0.001 lowest therapeutic dose and 10 ppm).

Background On The TOC Data Set

The TOC data set used in this analysis was collected from filling equipment for semi-
solid pharmaceutical products. TOC is potentially the ideal analytical method for
evaluating the cleanliness of equipment surfaces as it will detect almost any possible
source of organic carbon present on the equipment. Since the vast majority of
pharmaceutical substances/products (active pharmaceutical ingredients, excipients,
etc.) contain significant amounts of organic carbon, TOC can be used to detect all these
compounds in one analysis. TOC can also detect residues of any cleaning agents
containing organic carbon. The sensitivity of some TOC instruments is in the very low
parts per billion (ppb or μg/mL) range, so there is always a possibility of detecting low
organic carbon signals in cleaning samples even after scrupulous cleaning. This also
makes TOC data potentially amenable to statistical analysis, including process capability
analysis and statistical process control.

These TOC data were collected from four filling lines, and there was one cleaning SOP
(manual cleaning) used for all the filling equipment in this study. This data set consisted
of 155 swab samples taken from multiple sites on this filling equipment after cleaning,
ranging from nine to 13 samples per cleaning run. Figure 1 shows an example diagram of
one filling line with a typical sampling scheme.

Fig. 1 - Example Diagram of Sample Sites for a Filling Line

The intent was to use these data to determine the process capability of the cleaning
process and then set a statistical process control (SPC) limit for TOC swab results.
Initially, these data were given to a company statistician for analysis. Figure 2 shows an
empirical probability density plot that was created by the statistician. The bulk of the
data appeared to be normally distributed with a small tail of data to the right. However,
the statistician reported back that these data were not normally distributed. The
statistician suggested that an upper control limit (UCL) of 900 ppb could be set based
on the 95th percentile of the data.
Fig. 2 - Empirical Probability Density Plot of TOC Swab Data - Data is in parts
per billion (ppb).

Consequently, it was decided to set the UCL at 1,000 ppb, or 1 ppm. A limit of 1 ppm was
deemed appropriate based on the fact that all of the data were in the ppb range, with
few, if any, data ever in the ppm range. Additionally, the experience of collecting TOC
data had made 1 ppm a "psychological threshold" between typical and suspect data.
And, finally, 1 ppm was easy to remember as well as being statistically justifiable.

That was the extent of the statistical analysis of these data at the time. However, the
advent of Six Sigma and Process Excellence programs has brought statistical knowledge
and understanding to pharmaceutical manufacturing, along with access to powerful
statistical software such as Minitab JMP and the R programming language. The tools
and techniques of these programs greatly simplify the sophisticated analysis of data sets
like these, as we will see below.

Using Six Sigma Approaches To Evaluate The TOC Data

In the Measure phase of the Six Sigma DMAIC process, the first step is a "first pass
analysis," where an initial look is taken of the collected data to see what they can tell you
about your process. Such a first pass analysis should always be a graphical one, as this
can quickly reveal important information about your data. In Six Sigma programs, it is
recommended that you "slice and dice" the data until these analyses reveal something to
you. In our first pass, a simple histogram, a box plot, and a probability plot were created.

Figure 3 shows a histogram of the TOC data set (with a corresponding box plot above it)
that was generated using the R programming language. A visual examination of the
histogram reveals that the majority of the data may be normally distributed in a narrow
range around 150 ppb, along with a number of outlier data points. In the box plot, the
mean (solid blue vertical line) and the median (dotted blue vertical line) indicate that
these data are skewed somewhat to the right (the mean is greater than the median) and
identifies the suspected outliers in the histogram as actual outliers (circles). At the time
of these studies, these outliers were considered to be "hot spots" where the cleaning had
not been as effective as for the majority of the sample locations.

Fig. 3 - Histogram (with Marginal Box Plot) of TOC Data with "Hot Spots"

Figure 4 shows a normal probability plot of these TOC data for a normal distribution,
which reveals that these TOC data are not normally distributed. This probability plot
compares the percentile ranks of the TOC data against the percentile ranks of the
normal distribution. The TOC data points should visually fall along the red line.2

The Anderson-Darling test was chosen to evaluate the data for the normal distribution
analysis, as it is known to be more effective in detecting departures in the tails of a
distribution. The resulting P-value for the Anderson-Darling test was <0.005, so one
would reject the null hypothesis that these data were normally distributed.
 Fig. 4 - Probability Plot of TOC Data with "Hot Spots"

It may well be expected that TOC data should be normally distributed as they are the
sums of multiple independent random variables (residue variability, sampling
variability, dilution variability, analytical variability, etc.), which, according to the
Central Limit Theorem, will tend toward normal distributions.3 While the majority of
these TOC data appeared to be normally distributed in the probability density plot in
Figure 2, the probability plot in Figure 4 clearly indicates that they are not, both visually
and using a formal statistical test for normality. This departure from normality is, in all
likelihood, due to the presence of these "hot spots" or outlier data points. This is our
first indication that these data are not exhibiting random variability ("common cause")
and that there is/are some "special cause(s)."

Although none of these data points actually failed the cleaning validation acceptance
criteria used at that time, these "hot spots" were very noticeable and were considered
substantially different from the other data collected. In fact, during the course of these
studies, it became an expectation that all TOC data should be in the range of 100 to 250
ppb (within the normal-looking data seen in Figure 3) and any data above 1 ppm were
not expected and, if seen, were immediately suspicious.

These TOC data, including the "hot spots"/outliers, were analyzed for their process
capability using an upper specification limit of 1,000 ppb (1 ppm). The 1 ppm limit was
chosen for this analysis for demonstration purposes because it had been previously
suggested as an upper control limit. The graphical output of Minitab is shown in Figure
5.

Fig. 5 - Process Capability Analysis of TOC Data Set with "Hot Spots" - The
Minitab report lists the PPU (process performance upper) rather than the Cpu (process
capability upper). Note that a confidence interval (CI) for the process capability can also
be calculated. At the 95% confidence level, the lower bound (LB) is 0.38. It should be
considered a good cleaning validation practice to report the LCI as this represents the
worst possible case based on the sample size.

(Note: The shape of the histogram appears to indicate non-normal data.)

(Note: CPU is based on the subgroup standard deviation and PPU is based on the overall
standard deviation.)

This analysis shows that the mean of these data was 245 ppb, with a standard deviation
of 568 ppb. It should be immediately noticed that the standard deviation is more than
twice the value of the mean, which corresponds to a relative standard deviation (%RSD)
of 232%! The values of the mean and especially the standard deviation have been
significantly affected by these "hot spot"/outlier data, resulting in an upward shift in the
value for the mean and a severely magnified value for the standard deviation. As the
mean and standard deviation are used in the process capability calculation, the process
capability has been significantly affected as well.

We can see that the process performance capability (Ppk/PPU) is less than 1 (0.44). As
the number of samples (N) is also available, depending on the expectation set for
process capability, a lower one-sided confidence bound can also be calculated for this
process capability index. In this case we see a LB of 0.38. A value of 1 is considered
inadequate in Six Sigma programs and requires remediation. The process capability
value must be at least 1.33 to be considered acceptable. This process capability value of
0.44 also resulted in an expected cleaning performance of 92,164 failures per million
samples, or over 9 percent of the time, which is clearly unacceptable.

As noted above, this data set would not be considered normally distributed, mostly due
to these outlier values. It is generally not considered legitimate to perform statistical
analyses that assume a normal distribution on non-normal data. There are several
options that can be used in these situations:4,5

1. Transform the data to a normal distribution. (Note: When this strategy is

followed, any limits for the data should also be transformed.)

• The Box-Cox transformation raises the data to either the square, the square
root, the log, or the inverse.
• The Johnson transformation selects an optimal transformation function.

2. Identify the data distribution and evaluate the data using a non-normal
distribution model., e.g., lognormal, gamma distributions.

3. Evaluate the data using a non-parametric method., e.g., empirical percentile

method.

We will examine all three options.

Data Transformation
Both Box-Cox and Johnson transformations were used to transform the TOC data to
normality. Figures 6a and 6b show the TOC data after Box-Cox and Johnson
transformations, respectively.
Fig. 6a and 6b - Process Capability Analysis of TOC Data Set with "Hot Spots" after (a)
Box-Cox Transformation and (b) Johnson Transformation

* USL was transformed along with the data

For the Box-Cox transformation, the equation X(λ) = (Xλ – 1)/ λ was used for
transforming the data and the upper specification limit (USL) of 1,000 ppb using the
lambda (λ) value of 0.1. The process capabaility has improved (0.74), as well as the
lower bound (0.65), but both are still well below the capability requirement of 1.33. This
process capability value of 0.74 also indicates an expected cleaning performance of
13,570 failures per million samples, or over 1 percent of the time, which is still
unacceptable.

For the Johnson transformation, the optimal equation in the title of the graph (Figure
6b) was used to transform each data point as well as the USL that was used (1,000 ppb)
and this resulted in data that had the best fit for a normal distribution. The process
capability is 0.67, with a lower bound of 0.59, but both are still well below the value of
1.33. This process capability value of 0.67 indicates an expected cleaning performance of
22,011 failures per million samples, or over 2 percent of the time, which is still
unacceptable.
Non-Normal Distribution
To identify a best-fitting distribution for the TOC data, the Individual Distribution
Identification feature of Minitab was used. Based on the goodness of fit (GOF) test
results, none of the parametric distributions fit the data well. The GOF results are shown
in Table 1. As seen in the table, the P-value of 0.265 (&GT0.05) suggests that the
Johnson transformed data fit the normal distribution well.

Table 1: Goodness of Fit Test Results for Distribution Identification

AD = Anderson-Darling, LRT P = Likelihood-Ratio Test (low LRT P values indicate that

the fit is improved by the addition of a second or third parameter to the model)

For comparison purposes, the process capability was evaluated assuming lognormal and
gamma distributions for the data.

Figure 7 shows the TOC data evaluated using a lognormal distribution.

 Fig. 7 - Process Capability of TOC Data Set with "Hot Spots" Lognormal
Distribution - a lognormal distribution is a probability distribution of variables whose
logarithms follow a normal distribution. Many data follow a lognormal distribution.

The process capability using the lognormal (0.68) is almost identical to the value
obtained by the Johnson transformation (0.67) and is also well below the value of 1.33.
This process capability value of 0.68 also indicates an expected cleaning performance of
19,355 failures per million samples, or almost 2 percent of the time, which again is
unacceptable.

Figure 8 shows the TOC data evaluated using a gamma distribution.

 Fig. 8 - Process Capability of TOC Data Set with "Hot Spots" using the
Gamma Distribution - Gamma distributions are a family of right-skewed, continuous
probability distributions (exponential, Erlang, and chi-squared distributions) and are
useful in situations where something has a natural minimum of 0, or a lower boundary,
such as is often found with cleaning analytical data.

The process capability assuming a gamma distribution (0.72) is somewhat better

(higher) than the values obtained assuming the Johnson transformation (0.67) or the
lognormal distribution (0.68) but is still well below the value of 1.33. This process
capability value of 0.72 also resulted in an expected cleaning performance of 19,355
failures (same as the lognormal) per million samples, or almost 2 percent of the time,
which, again, is still unacceptable.

Non-Parametric Method
For the process capability using a non-parametric approach (empirical percentile
method), the data were imported into Excel and the calculations performed as shown in
Table 2. This approach yielded a process capability of only 0.21, which is the worst of the
four approaches.
Table 2 - Process Capability by the Empirical Percentile Method using Excel

Table 3 summarizes the process capabilities of each of these approaches and the P-
values calculated for the GOF for the distributions.

Table 3- Process Capability Values and Goodness of Fit P-Values for

Different Approaches

Interestingly, there is very little difference in the process capabilities calculated using
the Johnson transformation and either of the non-normal distributions. However, only
the Johnson transformation had an acceptable P-value (0.265), indicating the
transformed data fit the normal distribution well, so this analysis would typically be the
one chosen.

Evaluation Of TOC Data Using The Process Capability Scale

A scale from 1 to 10 for potential use in cleaning FMEAs has been developed that derives
scores on a scale directly from the cleaning process capability (Cpu).6 This calculation is
performed by simply taking the reciprocal of the Cpu and multiplying by 10 (Figure 9).
 Fig. 9 - Process Capability Scores for TOC Data Set with "Hot Spots”

Process Capability Score = 1/Cpu x 10

In the development of this process capability scale, the midpoint was set to a score of 5.
This score corresponds to a process capability of 2, which is equivalent to "Six Sigma" in
Operational Excellence programs. Scores greater than 5 on this scale are considered
increasingly poorer than Six Sigma and scores lower than 5 are considered increasingly
better than Six Sigma.

The results of the process capability analysis for the TOC data above were analyzed and
resulted in scores ranging from 13.9 to 22.7, all of which are extremely poor and off the
top of the scale. The score for the empirical percentile method (48.7) was too far off the
chart to plot. Such results indicate, regardless of the data distribution model used, that
cleaning improvements are absolutely necessary.

Evaluation Of TOC Data Using The Shirokizawa Matrix

An additional approach has also been developed using the toxicity scale7 and the process
capability scale6 for determining the level of effort, formality, and documentation (as
suggested in the 2021 draft ICH Q9 (R1)) necessary for cleaning validation based on the
level of risk. The toxicity scale and the process capability scale have been combined into
a matrix called the Shirokizawa Matrix.8 The toxicity score of a product and the process
capability score for its cleaning process can be plotted on this matrix. Eight groupings
have been created in the matrix that suggest a level of effort, formality, and
documentation necessary for cleaning validation based on the location of the plotted
point (Figure 10).

Fig. 10 - Shirokizawa Matrix for TOC Data Set with Hot Spots. Note: The
location of the circle labeled "TOC Data" is deceptive as this point is actually far off the
process capability scale and the data cannot be plotted on this matrix.

As seen in Figure 10, the process capability score for the TOC data puts it at (actually,
off) the top of the scale and corresponds to Group 1 or Group 2 of the Shirokizawa
Matrix. Toxicity scores of &GT6 up to 10 (Group 2) would require dedicated facilities or
equipment and toxicity scores of <6 down to 1 (Group 1) would require extensive
cleaning validation efforts. Neither of these are desirable options, especially considering
these were topical formulations of low-hazard compounds. In such situations, cleaning
process improvements are clearly necessary. The ASTM E3106 Standard discusses risk
reduction activities, including cleaning process development, and these activities should
be undertaken in situations such as this.

Importance of Cleaning Process Improvement

We will now examine why cleaning process improvements are not only required of
companies in situations like this but should be highly desirable for all companies to
perform. What if cleaning process improvements had been performed on the cleaning
process and these "hot spots" no longer occurred?

To explore this question, these "hot spot" data (all data above 400 ppb) were reviewed
to determine where and when they occurred and if there were any relationships that
could help guide the improvement with the cleaning process. These "hot spots" are
shown in Table 4.

Table 4 - TOC "Hot Spots" - The table shows what filling line the "hot spots"
occurred on, what run they occurred on, what equipment they occurred on, and the TOC
result for that sample.

There were 14 "hot spot" data points that occurred during a total of 13 qualification runs
that were performed for this cleaning process. These "hot spots" occurred on all four
filling lines, across the three or four qualification runs for each line, and on 12 different
pieces of equipment. Of the 14 "hot spots," 12 were on different pieces of equipment and
only two locations had repeated high results (pump housing head and the filler valve
assembly). The pump housing head was considered an "easy to clean" piece of
equipment and the filler valve assembly was considered a "hard to clean" piece of
equipment. It was observed during these qualification studies that these "hot spots"
were not specifically associated with hard to clean pieces of equipment and could occur
anywhere, including on surfaces that were considered easy to clean.

Fig. 11 - Histogram of TOC Data for all Four Filling Lines -"Hot spot" data occur
across all four filling lines, while the majority of TOC data are around 150 ppb.

The "hot spot" data were found to occur across all filling lines (Figure 11). It was also
observed that pieces of equipment that would typically be considered hard to clean
tended to have the lowest results. This may indicate that the operators focused more
attention on the hard to clean pieces of equipment, giving less attention to the "easy to
clean" pieces of equipment, which resulted in these "hot spots" occurring sporadically.
These "hot spots" were also not associated with any particular piece of equipment, so
this was not a specific equipment design issue (Figure 12).
 Fig. 12 - Histogram of TOC Data for Filling Equipment - "Hot spot" data occur
across all pieces of equipment, while the majority of TOC data are around 150 ppb.

These "hot spots" were also not associated with any particular product, as different
products were used in the qualification runs on the different lines. The results for the
other equipment and for the other runs were very low.

One particular run on Line 1 had five "hot spots." This leads to the conclusion that while
the cleaning process was quite capable of cleaning this equipment acceptably, the
cleaning performance was variable from run to run. So, in these cleaning studies,
operator variability seemed to possibly present an issue and proper training could
resolve this. In other words, this poor process capability appears to be something that
could be improved.

To observe what effect cleaning improvements would have on the process capability,
these 14 "hot spot" data points were removed from the data set and the process
capability analyses were performed again. Also of interest is where in the Shirokizawa
Matrix such improvements would locate the improved cleaning process and what effect
this would have on the level of qualification efforts necessary. Figure 13 is a histogram of
the data set with the 14 "hot spots" removed.
 Fig. 13 - Histogram of TOC Data "Cleaned" of "Hot Spots"

The mean of these data was reduced to 143 ppb, with a standard deviation of only 70
ppb now. The standard deviation is now half the value of the mean, which corresponds
to a relative standard deviation (RSD) of 49%. Clearly, the data appear much more
normally distributed without these data.

Figure 14 shows a process capability analysis of these TOC data cleaned of the "hot
spots."
 Fig. 14 - Process Capability Analysis of TOC Data Set "Cleaned" of "Hot
Spots"

While the RSD is still large, the mean and standard deviation have been positively
affected by the removal of these "hot spots." The process capability (Ppk/PPU) is now
4.06 with an LCI of 3.58. This process capability resulted in an expected cleaning
performance of 0.00 failures per million samples, or less than 1 in 100 million samples.
 Fig. 15 - Normality Test of TOC Data "Cleaned" of "Hot Spots"

Although the data visually appear normal, with the data falling much better along the
probability plot, the P-value for the Anderson-Darling test (Figure 15) still indicates a
low probability of normality (<0.005 instead of &GT0.05).

It is well known that the normality test is very sensitive to outliers, or any abnormalities
in the data set, which can result in low P-values, and false rejection of the null
hypothesis, in these cases. A visual examination of the histogram (Figure 13) and the
probability plot (Figure 15) reveals what appears to be possible curvature in several
places, so it was suspected that the data set may actually consist of bimodal, or even
multi-modal, data. JMP software was used to perform both Normal 2 Mixture
Distribution and Normal 3 Mixture Distribution analyses on the data set (Figure 16).
Fig. 16 - Fitted Normal 2 and 3 Mixture Plots and QQ Plot for "Cleaned" TOC
Data

Figure 16 shows the fitted plot, which shows the possible presence of three normal
distributions within the data set. The quantile-quantile (QQ) plot shows strong
normality for these three distributions. JMP also estimates a separate mean and
standard deviation and a proportion of the whole for each distribution (Table 5).

Table 5 - Parameters and Estimates of the Normal 3 Mixture Distributions

Since this analysis provides the parameters for each distribution, these can be used to
identify the individual results belonging to these possible distributions and allow an
exploration of these data that could potentially identify the source of these distributions.

The means ± 3 standard deviations for Distribution 1 (low data) and Distribution 3 (high
data) were calculated, and those parts whose TOC data were found between these means
± 3 standard deviations were tabulated, along with the line and run number they were
from (Table 6). This analysis could reveal which pieces of equipment, what lines, or
which runs resulted in the low data for Distribution 1 or the high data for Distribution 3.
 Table 6 - Parts, Lines, and Runs Associated with Distribution 1 and
Distribution 3

A review of the data in Table 6 did not identify any particular parts associated with
Distribution 1 (low TOC) or Distribution 3 (high TOC). The same parts showed up in
both distributions fairly equally.

Comparison of the lines revealed that Distribution 1 (low TOC) was associated with line
1 and line 4 at 38% and 46% of the time, respectively. Distribution 3 (high TOC) was
associated with line 2 and line 3 at 38% and 29% of the time, respectively. If there was
an equal probability, then each line would be expected to be 25%. The same "hardest-to-
clean" product was used for the qualification runs for line 1 and line 4, which may
explain why their results were similar. Different products were used for lines 2 and 3.

Comparison of the runs revealed that Distribution 1 (low TOC) was strongly associated
(75%) with run 1 for all lines. Distribution 3 (high TOC) was associated with runs 2 and
3 at 48% and 43% of the time, respectively, for a total of 91%. These results could
indicate a higher sense of importance by the operator and more careful cleaning during
the first qualification runs resulting in the lower TOC data for these runs. This may have
been an example of the so-called "Hawthorne Effect," in which workers are more
productive when they know they are being observed.9 While there has been some doubt
cast on this phenomenon in recent times,10 this might provide some explanation for the
discrepancy between the results for the first runs and subsequent runs. While there were
no metadata (e.g., shift, operator, analyst, etc.) collected during these studies that could
demonstrate that this phenomenon had occurred, this phenomenon should be
considered when designing monitoring or verification programs for cleaning processes.

Taking the process capability results for the data "cleaned" of the 14 "hot spot" data
points and plotting it on the Cpu-based process capability scale, we can see that the
score is now 2.5 on the scale (Figure 17). This is well beyond a Six Sigma process and can
be considered excellent cleaning and a low risk to patient safety.

The process capability score for the TOC data "cleaned" of "hot spots" locates it toward
the bottom of the scale now (Cpu Score = 2.5), and this result was plotted on the
Shirokizawa Matrix (Figure 18) to determine what the suggested level of effort,
formality, and documentation should be at this level of process capability.

Fig. 17 - Process Capability Score for TOC Data Set with "Hot Spots"
Removed
Plotting this process capability score on the Shirokizawa Matrix (Figure 18), we find that
the TOC data now falls into Group 6 for toxicity scores of &GT6 up to 10, which would
require visual inspection supported by periodic monitoring, and into Groups 7 and 8 for
toxicity scores of <6 down to 1, which would also require only visual inspection
supported by periodic monitoring. These are highly desirable options, again considering
these were topical formulations of low-hazard compounds.

Fig. 18 - Shirokizawa Matrix for TOC Data Set "Cleaned" of Hot Spots

The options in the Shirokizawa analysis in Figure 18 for the "cleaned" TOC data are
clearly very desirable. But these options can only be justified through excellent
process capability results, which requires excellent cleaning processes, which
in turn requires excellent cleaning process development. Cleaning process
development studies as required in the ASTM E3106 Standard, in combination with risk
reduction activities, can help companies achieve such results and justify these simpler
control strategies.
Clearly, any cleaning process improvement work that can eliminate variability, or "hot
spots" such as were found in these data, reduces the risk of cross contamination that
could potentially impact patient safety. And any such results as were found in Figure 10
indicate that cleaning process improvements absolutely must be undertaken.

Summary

The TOC data set examined in this article is clearly much more complex than a cursory
examination of a simple probability distribution graph, such as in Figure 2, can reveal. If
the statistical tools used in this analysis were available at the time that these data were
generated, a deeper investigation of the causes for the outliers and the multi-modal
nature of the data could have been revealed. And if additional metadata had been
collected along with the swab samples, an even deeper analysis would have been
possible.

One of the goals of the ASTM E3106 Standard Guide was to provide a framework for
implementing the ICH Q9 Quality Risk Management and FDA's Process Validation
approaches for cleaning processes. The calculation of process capability is an important
part of the risk assessment of cleaning processes and is consistent with ICH Q9 and
FDA's 2011 guidance. As stated above, ASTM E3106 Standard provides guidance on
performing cleaning process development studies, and excellent process capabilities are
easily within the grasp of any company willing to make the effort. If industry and
regulators adopt the Shirokizawa Matrix and its control strategy concepts, then
companies unwilling to make the effort to improve their cleaning will be required to
expend considerable effort on continuing cleaning qualification/verification activities.
Therefore any "relaxation of cleaning efforts," as some regulators have feared,
should come with significant operational costs to those companies.

Peer Review

The authors wish to thank James Bergum, Ph.D, Joel Bercu, Ph.D., Sarra Boujelben,
Gabriela Cruz, Ph.D., David Dolan, Ph.D., Mallory DeGennaro, Parth Desai, Jayen
Diyora, Kenneth Farrugia, Andreas Flueckiger, M.D., Christophe Gamblin, Ioanna-
Maria Gerostathes, Ioana Gheorghiev, M.D., Igor Gorsky, Jessica Graham, Ph.D.,
Laurence O'Leary, Ajay Kumar Raghuwanshi, Kailash Rathi, Siegfried Schmitt, Ph.D.,
and Basundhara Sthapit, Ph.D., for reviewing this article and for providing insightful
comments and helpful suggestions.

References

1. Walsh, Andrew, Miquel Romero Obon and Ovais Mohammad "Calculating The
Process Capabilities Of Cleaning Processes: A Primer" Outsourced Pharma,
November 1, 2021.

2. Ghasemi, A., & Zahediasl, S. "Normality tests for statistical analysis: a guide for
non-statisticians". Int J Endocrinol Metab, 10(2) 2012
 3. Lyon, Aidan, "Why are Normal Distributions Normal?" Brit. J. Phil. Sci. 65
(2014), 621–649

4. Pyzdek, Thomas “The Six Sigma Handbook” 2nd Edition 2003 McGraw Hill

5. Johnson, Lou ”Modeling Non-Normal Data Using Statistical Software” R&D

Magazine August 2007

6. Walsh, Andrew, Ester Lovsin Barle, David G. Dolan, Andreas Flueckiger, Igor
Gorsky, Robert Kowal, Mohammad Ovais, Osamu Shirokizawa, and Kelly
Waldron. "A Process Capability-Derived Scale For Assessing Product Cross-
Contamination Risk In Shared Facilities" Pharmaceutical Online August 2017

7. Walsh, Andrew, Ester Lovsin Barle, Michel Crevoisier, David G. Dolan, Andreas
Flueckiger, Mohammad Ovais, Osamu Shirokizawa, and Kelly Waldron. "An
ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared
Facilities" Pharmaceutical Online May 2017

8. Walsh, Andrew, Thomas Altmann, Ralph Basile, Joel Bercu, Ph.D., Alfredo
Canhoto, Ph.D., David G. Dolan Ph.D., Pernille Damkjaer, Andreas Flueckiger,
M.D., Igor Gorsky, Jessica Graham, Ph.D., Ester Lovsin Barle, Ph.D., Ovais
Mohammad, Mariann Neverovitch, Siegfried Schmitt, Ph.D. and Osamu
Shirokizawa" The Shirokizawa Matrix: Determining the Level of Effort,
Formality and Documentation in Cleaning Validation" Pharmaceutical Online
December 2019

9. Mayo, Elton "Hawthorne and the Western Electric Company, The Social
Problems of an Industrial Civilisation," Routledge, 1949

10. Levitt, S. D.; List, J. A. (2011). "Was there really a Hawthorne effect at the
Hawthorne plant? An analysis of the original illumination experiments"
American Economic Journal: Applied Economics. 3: 224–238.
doi:10.1257/app.3.1.224

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